Navigating the regulatory and development pathways for drug-device products

David Lee began his path to CEO of Lumicell in 1999, when his wife was diagnosed with cancer. She passed away in 2003, while Lee was working in the semiconductor industry. He decided it was time for a career change.

More than a decade later, Lee holds the corner office at a company that is developing a hand-held imaging system to detect residual cancer and treat it in real-time. The product is in Phase IIb testing and in 45 patients, the device has not yet missed any cancer.

“We have a 100% batting average,” Lee told a crowd last week at MassBio’s event, The Convergence of Medical Devices & Drugs: The Future of Combination Products.

When Lee set out to create a drug-device product that would detect and treat residual cancer in real-time, his team had to face the complex questions that surround the combinations product space. After a lot of consideration, Lee decided that the company would need to develop the device and the drug, instead of partnering or licensing an existing drug.

When other competing companies looked in one direction for answers, the Lumicell team searched for a different solution. At the time, long wave infrared was a hot topic in fluorescent microscopy because it could penetrate deep into the tissue, according to Lee. Instead, his team decided to use short wave infrared to detect cancer on the surface of the tumor.

Lee credited the company’s ability to make bold decisions about its development strategy thanks to a team of colleauges with diverse backgrounds.

“The team could address everything. We had all the skills in the world. Clinical, medical, biological, optical, physics, electronics, they were all right there.”

Looking ahead, Lee said he doesn’t expect the company to stop at operative surgery.

“One thing about concurrent engineering, spending all those hours in the OR and understanding the surgical needs is that you look around outside the OR at all the other equipment, you start wondering – why can’t this be done smarter and more simply?” he said. “It’s just the beginning, and I really believe that taking the time to identify the unmet need very clearly and being bold about addressing it completely, which does mean bringing together different disciplines, pays off handsomely.”

Advice from the heavy-hitters and from the up-and-comers

From pharmaceutical giants like Shire (NSDQ:SHPG) to young start-ups like PanTher Therapeutics, companies in the combination product space face a unique set of challenges along the development and regulatory pathways.

Dr. Ailis Tweed-Kent, CEO and founder of Cocoon Biotech, said that thinking ahead and anticipating the final result is crucial to success in the drug-device arena.

“I think it’s really important from the start to think about your pathway and commercially where you want to end up,” she said.

Cocoon Biotech is leveraging silk as a drug delivery platform to alleviate the symptoms of osteoarthritis. The company licensed the intellectual property from Tufts University and Tweed-Kent said there is an advantage to sharing IP with a partner.

“If you own that IP jointly, there’s sort of mutual incentive to bring that product to market,” she said.

That can be risky, patent attorney David Dykeman said, since IP ownership can get complicated if the relationship sours. He added that investing early in IP is a crucial step for any company.

“It helps you carve out your space, keep your competitors at bay, and it certainly is helpful if you’re trying to raise venture capital funding or enter into any license or joint development or collaboration agreement,” he said. “You need to make sure you’ve got freedom to operate before you’re going down the development path.”

Once a company begins development, it’s vital to maintain open communication between the device-makers and the drug-makers, according to Steve Bowman, the device program lead at Shire.

“Many times we have teams that are in Phase III trials, halfway through enrollment, and then they say, ‘Oh gee, wouldn’t it be great if we put this in an auto-injector?’ We tell them, ‘Wish you had told us that 3 years ago.’ Again, communication is key.”

Regulation and reimbursement: choosing the right path

The regulatory pathways for drug-device combination products can be confusing – generally, companies decide to pursue a drug pathway or a device pathway based on the primary mode of action. Dykeman said that there is a general belief in the field that device pathway is quicker and cheaper, but that isn’t always the case.

“If the key mechanism of action is a pharmaceutical and if you get on the device side, you might have quicker device trials, but then they’re going to make you do the active ingredient trials anyway. You’ve delayed yourself,” he said.

To avoid any potential regulatory setbacks down the road, Bowman said that the folks at Shire make it a point to keep regulatory authorities in the loop.

“Our approach has always been to reach out to the FDA, reach out to the European authorities, to Japan, Canada, whatnot to get their feedback because they’re not going away,” he said. “The better relationship you can have with them just is going to make your overall timeline from start to finish much smoother and more predictable.”

Keeping the FDA up to speed is something Laura Indolfi and her team at PanTher Therapeutics have been doing from the start. The company is developing an implantable device that can deliver chemotherapy directly to the site of a pancreatic tumor. She said the company decided to pursue a 505(b)(2), since the product’s primary mode of action is a drug.

“Regulatory kind of defines the roadmap for the next foreseeable future,” Indolfi said.

Although guidance for combination products scored a win with the passage of the 21st Century Cures Act last year, experts in the regulatory space pointed out that there is still a lot left to be done.

“There is a clear need to define and harmonize regulations for combination products globally,” Raina Dauria, global regulatory affairs leader at Ethicon, said. “Honestly, even the current non-combination product regulations aren’t harmonized globally, so it’s not realistic to expect this to happen anytime soon.”

Maneuvering through complex regulatory systems and developing an innovative combination product isn’t enough to guarantee a return for investors. To ensure that their investors and potential patient population is best served, companies need to consider the path to reimbursement and it’s not always about having the most effective product.

“[Payers are] making trade-offs and decisions that are not always about the best and most effective, but it’s now about what can we afford and what’s the best we can deliver based on those economic variables,” Diane Francis, senior director of health economic solutions at Ethicon, said. “What we have found that is really critical that you start the discussion regarding your reimbursement pathway as well as your economic value proposition in the very first stage.”

Most drug-device companies establish very clear clinical effectiveness endpoints, Francis said, but companies need to incorporate health economics and real-world data as a part of their testing paradigm.

“Think early in your regulatory studies about your health economics data, plan for specific health economics studies, but also, as you look at developing appropriate tools and models and conversations with the economic buyer, think about the role of real-world data in helping you generate evidence that proves out your hypothesis in the real world,” Francis said. “That’s increasingly a key part of how decision-making is being made.”